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Peer-reviewedCC BY-NC-NDNature Medicine

Emergence and spread of Plasmodium falciparum PX1 polymorphisms associated with decreased susceptibility to antimalarials in Uganda

  • Karamoko Niaré1,2
  • Bersabeh D. Tafesse3
  • Mayland Treat3
  • Jacob M. Sadler4
  • Martin Okitwi5
  • Stephen Orena5
  • Victor Asua5,6
  • Oriana Kreutzfeld3
  • Jenny Legac3
  • Jacob Marglous7
  • Samuel L. Nsobya5
  • Adoke Yeka8,5
7 more authors
  • Dave Richard9
  • Michael T. Ferdig10
  • Angana Mukherjee10
  • Philip Jon Rosenthal3
  • Jonathan J. Juliano11,12,4
  • Jeffrey A. Bailey13,7
  • Melissa D. Conrad14,15
15 affiliations
  1. 1Center for Computational Molecular Biology, Brown University, Providence, RI, USA. [email protected]
  2. 2Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA. [email protected]
  3. 3Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
  4. 4Institute for Global Health and Infectious Diseases, University of North Carolina, Chapel Hill, NC, USA
  5. 5Infectious Diseases Research Collaboration, Kampala, Uganda
  6. 6Institute for Tropical Medicine, University of Tubingen, Tubingen, Germany
  7. 7Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA
  8. 8Department of Disease Control and Environmental Health, Makerere University, Kampala, Uganda
  9. 9Department of Microbiology-Infectious Diseases and Immunology, Université Laval, Quebec, Quebec, Canada
  10. 10Department of Biological Sciences, Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, USA
  11. 11Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
  12. 12Division of Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
  13. 13Center for Computational Molecular Biology, Brown University, Providence, RI, USA
  14. 14Department of Medicine, University of California, San Francisco, San Francisco, CA, USA. [email protected]
  15. 15Johns Hopkins Malaria Research Institute, Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. [email protected]
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Abstract

Artemisinin-based combination therapies are the cornerstone of malaria treatment and control. In Africa, artemether-lumefantrine is the most widely used first-line artemisinin-based combination therapy, but its efficacy in Uganda is increasingly threatened by the emergence of artemisinin partial resistance and reduced lumefantrine susceptibility. To identify loci contributing to this decreased susceptibility, here we assessed signatures of selection in 157 whole-genome sequences of Plasmodium falciparum from Uganda. Although extended haplotypes were observed around Kelch13 C469Y and A675V mutations, the strongest signal of recent selection was centered on a segment of chr. 7 encoding the phosphoinositide-binding protein (PX1, PF3D7_0720700). A haplotype, represented by three PX1 mutations (L1222P, M1701I and D1705N) and two deletions (designated PIN), was first seen in 2008 and rapidly increased, reaching a prevalence >50% in northern Uganda by 2016 and eastern Uganda by 2023. PIN-carrying parasites showed significantly decreased ex vivo susceptibilities to lumefantrine, mefloquine and dihydroartemisinin, an active metabolite of artemether. A parasite strain in which px1 was disrupted in vitro showed increased susceptibility to the three drugs. Thus, PX1 polymorphisms appear to impact on the susceptibilities of African malaria parasites to key drugs.

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Cite

BibTeXRIS
BibTeX
@article{niare2026emergence,
  title = {{Emergence and spread of Plasmodium falciparum PX1 polymorphisms associated with decreased susceptibility to antimalarials in Uganda}},
  author = {Karamoko Niaré and Bersabeh D. Tafesse and Mayland Treat and Jacob M. Sadler and Martin Okitwi and Stephen Orena and Victor Asua and Oriana Kreutzfeld and Jenny Legac and Jacob Marglous and Samuel L. Nsobya and Adoke Yeka and Dave Richard and Michael T. Ferdig and Angana Mukherjee and Philip Jon Rosenthal and Jonathan J. Juliano and Jeffrey A. Bailey and Melissa D. Conrad},
  journal = {Nature Medicine},
  year = {2026},
  month = aug,
  doi = {10.1038/s41591-026-04590-5},
  url = {https://doi.org/10.1038/s41591-026-04590-5},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Emergence and spread of Plasmodium falciparum PX1 polymorphisms associated with decreased susceptibility to antimalarials in Uganda
AU  - Karamoko Niaré
AU  - Bersabeh D. Tafesse
AU  - Mayland Treat
AU  - Jacob M. Sadler
AU  - Martin Okitwi
AU  - Stephen Orena
AU  - Victor Asua
AU  - Oriana Kreutzfeld
AU  - Jenny Legac
AU  - Jacob Marglous
AU  - Samuel L. Nsobya
AU  - Adoke Yeka
AU  - Dave Richard
AU  - Michael T. Ferdig
AU  - Angana Mukherjee
AU  - Philip Jon Rosenthal
AU  - Jonathan J. Juliano
AU  - Jeffrey A. Bailey
AU  - Melissa D. Conrad
PY  - 2026
DA  - 2026/08/17
JO  - Nature Medicine
DO  - 10.1038/s41591-026-04590-5
UR  - https://doi.org/10.1038/s41591-026-04590-5
AB  - Artemisinin-based combination therapies are the cornerstone of malaria treatment and control. In Africa, artemether-lumefantrine is the most widely used first-line artemisinin-based combination therapy, but its efficacy in Uganda is increasingly threatened by the emergence of artemisinin partial resistance and reduced lumefantrine susceptibility. To identify loci contributing to this decreased susceptibility, here we assessed signatures of selection in 157 whole-genome sequences of Plasmodium falciparum from Uganda. Although extended haplotypes were observed around Kelch13 C469Y and A675V mutations, the strongest signal of recent selection was centered on a segment of chr. 7 encoding the phosphoinositide-binding protein (PX1, PF3D7_0720700). A haplotype, represented by three PX1 mutations (L1222P, M1701I and D1705N) and two deletions (designated PIN), was first seen in 2008 and rapidly increased, reaching a prevalence >50% in northern Uganda by 2016 and eastern Uganda by 2023. PIN-carrying parasites showed significantly decreased ex vivo susceptibilities to lumefantrine, mefloquine and dihydroartemisinin, an active metabolite of artemether. A parasite strain in which px1 was disrupted in vitro showed increased susceptibility to the three drugs. Thus, PX1 polymorphisms appear to impact on the susceptibilities of African malaria parasites to key drugs.
SN  - 1078-8956
SN  - 1546-170X
SN  - 1744-7933
ER  -